A Study of Dalcetrapib in Patients Hospitalized for an Acute Coronary Syndrome - dal-OUTCOMES

Description:

Despite multiple attempts, no pharmacological agent thus far has been successful in increasing high-density lipoprotein (HDL) while reducing coronary events. Dalcetrapib is a cholesteryl-ester-transfer protein (CETP) inhibitor that has not shown off-target effects such as blood pressure elevation (noted with torcetrapib, another CETP inhibitor in the ILLUSTRATE trial) in early trials. The current trial was a phase III trial designed to assess the efficacy and safety of dalcetrapib on clinical outcomes in patients with recent acute coronary syndrome (ACS) who were already on background evidence-based therapy.

Hypothesis:

Dalcetrapib would be superior to placebo in reducing cardiovascular events in patients with recent ACS who were already on background evidence-based therapy.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Age ≥45 years
  • ACS
  • Evidence-based management of LDL cholesterol
  • No restriction on entry level of HDL cholesterol

    Number of enrollees: 15,871
    Duration of follow-up: 31 months
    Mean patient age: 60 years
    Percentage female: 19%
    NYHA class: I/II (15%)

Exclusions:

  • Concomitant HDL cholesterol–raising therapy (niacin, fibrates, bile acid sequestrants, rimonabant, CETP therapy, or other)
  • Triglycerides ≥400 mg/dl

Primary Endpoints:

  • Primary outcome composite (time to first occurrence):
    - Coronary heart disease death
    - Nonfatal MI
    - Ischemic stroke
    - Hospitalization for unstable angina (with objective evidence of acute myocardial ischemia)
    - Cardiac arrest with resuscitation

Secondary Endpoints:

  • All-cause mortality
  • Coronary revascularization

Drug/Procedures Used:

Following a placebo run-in phase of 4-12 weeks, patients were randomized to either 600 mg/day of dalcetrapib or matching placebo, in addition to standard of care medications.

Concomitant Medications:

Statin (97%), aspirin (97%), thienopyridine (89%), beta-blockers (88%), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (79%)

Principal Findings:

This was an event-driven trial, which was terminated early due to futility. At this time, a total of 15,871 patients were randomized at 935 sites in 27 countries, 7,933 to dalcetrapib and 7,938 to placebo. About 24% had diabetes mellitus, 68% had hypertension, and 63% met criteria for the metabolic syndrome. About 85% of patients presented with biomarker-positive ACS, with a mean time from index hospitalization to randomization of 61 days. Revascularization was undertaken in 91% of patients. The mean baseline low-density lipoprotein (LDL) and HDL cholesterol values were 76 and 42 mg/dl, respectively. Median baseline high-sensitivity C-reactive protein (hs-CRP) was 1.5 mg/L.

Dalcetrapib resulted in a 30% increase in HDL cholesterol as compared with placebo, with a negligible effect on LDL cholesterol. Triglycerides increased by approximately the same amount in both arms (10%). Apolipoprotein A1 levels were increased by 10% after 3 months of treatment with dalcetrapib. The primary outcome of coronary heart disease death, nonfatal myocardial infarction (MI), ischemic stroke, hospitalization for unstable angina, and resuscitated cardiac arrest was similar between the dalcetrapib and placebo arms at 3 years (8.3% vs. 8.0%, hazard ratio 1.04; 95% confidence interval 0.93-1.16, p = 0.52). Individual outcomes including coronary heart disease death (1.5% vs. 1.6%, p = 0.66), nonfatal MI (5.2% vs. 5.1%, p = 0.80), all-cause mortality (2.8% vs. 2.9%, p = 0.90), coronary revascularization (8.5% vs. 8.5%, p = 0.97), and ischemic stroke (1.1% vs. 0.9%, p = 0.16) were similar between the two arms. Systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo over the duration of follow-up (p < 0.0001), although no differences were noted in plasma aldosterone, bicarbonate, or K levels. At 3 months, median hs-CRP was also higher in the dalcetrapib arm by 0.2 mg/dl (p < 0.001).

Interpretation:

The results of the large phase III dal-OUTCOMES trial indicate that raising HDL with dalcetrapib in patients with a recent ACS was not superior to placebo in improving cardiovascular (CV) outcomes in patients who were already on evidence-based secondary prevention measures. These results are similar to the negative results noted with torcetrapib (also a CETP inhibitor) in the ILLUMINATE trial and niacin in the AIM-HIGH trial (both in stable outpatients). Trials with dalcetrapib (in stable patients with coronary artery disease), and other HDL-raising agents such as anacetrapib (another CETP inhibitor), are ongoing. However, results of the other dalcetrapib trial will likely be moot since Roche recently discontinued further development of dalcetrapib. One of the biggest conundrums in cardiology is that although low HDL is associated with a higher risk of adverse CV outcomes, no pharmacological agent to date that raises HDL has demonstrated clinical efficacy in large outcomes trials. It remains to be investigated if other aspects such as HDL size and density are more important than absolute HDL levels in improving CV outcomes.

Similar to torcetrapib, dalcetrapib was also associated with off-target effects such as raised systolic blood pressure and elevated hs-CRP. This raises the possibility of a class effect for this off-target effect with CETP inhibitors. Further research is necessary to elucidate the mechanisms behind this effect.

References:

Presented by Dr. Gregory Schwartz at at the American Heart Association Scientific Sessions, Los Angeles, CA, November 5, 2012.

Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-2099.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Implantable Devices, SCD/Ventricular Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension

Keywords: Coronary Artery Disease, Follow-Up Studies, Apolipoprotein A-I, Heart Arrest, Biological Markers, Cholesterol, HDL, Confidence Intervals, Niacin, Hypertension, Oxazolidinones, Stroke, Myocardial Infarction, Acute Coronary Syndrome, Cholesterol, LDL, Sulfhydryl Compounds, Standard of Care, Quinolines, Metabolic Syndrome X, Cholesterol Ester Transfer Proteins, C-Reactive Protein, Bicarbonates, Medical Futility, Triglycerides, Diabetes Mellitus


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